Is USB1 p.Arg112Gln (c.335G>A) pathogenic?

USB1 p.Arg112Gln (c.335G>A) is classified Uncertain significance in USB1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-11-26). AlphaMissense: likely benign (0.0805); Ultra-rare (popmax 0.0329%, mid); Associated with Inborn genetic diseases.

What condition is associated with USB1 p.Arg112Gln (c.335G>A)?

USB1 p.Arg112Gln (c.335G>A) is associated with Inborn genetic diseases, poikiloderma with neutropenia (ClinVar).

How common is USB1 p.Arg112Gln (c.335G>A) in the general population?

USB1 p.Arg112Gln (c.335G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about USB1 p.Arg112Gln (c.335G>A)?

AlphaMissense predicts likely benign (score 0.0805) — an in-silico prediction, not a clinical call.

USB1 p.Arg112Gln

c.335G>A · rs142683238 · VCV1057267

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0805 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0805	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -6.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 1.8, phastCons 0.15
Regional constraint	o/e 0.95	unconstrained · MANE · 19 kb · p 0.36 · regional, not allelic
Overall
CADD	16.77	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00898% 145/1,613,898 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Admixed American	0.0217%	4,614
Remaining individualsnot grpmax-eligible	0.0192%	5,207
South Asian	0.0143%	7,006
European (non-Finnish)	0.00847%	11,800
East Asian	0.00669%	14,958
African / African-American	0.00267%	37,433

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: USB1
Protein: p.Arg112Gln
Coding: c.335G>A
MANE Select: NM_024598
dbSNP: rs142683238
Type: single nucleotide variant
Location: chr16:58009998 (GRCh38)
Gene constraint: LOEUF 1.016 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 83.91 · 5 PDB

Full USB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: poikiloderma with neutropenia

Similar variants

USB1 p.Arg112Trp Uncertain significance ★★ ⚠ same residue
USB1 p.Arg112fs Uncertain significance ★ same residue
USB1 p.Arg112Pro Uncertain significance ★ ⚠ same residue
USB1 p.Arg112= Likely benign ★ same residue
USB1 c.266-1G>A Pathogenic ★★ same condition
USB1 p.His208Arg Likely pathogenic ★★ same condition
USB1 p.Ala106Ser Uncertain significance ★★ ⚠ same condition
USB1 p.Ala218Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/usb1-p-arg112gln (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown